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Summary of the impact

Since 2008, pioneering contributions to the field of computational
chemistry for drug discovery
have been made by InhibOx Ltd., a spin-out company based on the research
of Graham Richards
and co-workers at the University of Oxford. InhibOx launched Scopius, the
world's largest
searchable virtual database of small-molecules (>112 million compounds)
and pioneered the use
of cloud computing for large-scale molecular modelling. The key impact for
customers of InhibOx
has been the reduced costs in identifying molecular leads for new drugs.
InhibOx's work has
helped to open up early stages of drug development to smaller companies;
75% of InhibOx's
clients are SMEs. Since 2008, InhibOx has received £ 2.8M in income and
investment.

Underpinning research

A common problem in small-molecule drug discovery is identifying useful
hits and leads.
Researchers have a difficult task in selecting compounds with therapeutic
potential from the billions
of possible starting points. Improving the selection of which molecules to
work with is a key part of
improving return on investment from early stage R&D spend, especially
for SME companies.
Computer-based screening is a potentially valuable tool for predicting
which molecules warrant
further investigation. Drug companies hold internal databases which may
hold tens of millions of
real or virtual molecules; however:

they are often narrowly concentrated around that company's areas of
expertise;

it can take 2-3 weeks to search the database (depending on computer
power available) to
predict whether a molecule has potential for binding to a particular
target;

developing a database in house is a specialised task and may be too
expensive for small
organisations (typically requiring two full-time staff for 5 years, or
around £400,000).

With these limitations in mind, in 2001, a project known as Screensaver
Lifesaver led by Graham
Richards set out to build a database of millions of drug-like molecules.
The database has two
sections: CSPACE, all molecules available commercially and VSPACE, virtual
molecules but with
known synthetic route. Software developed by the Richards group used the
idle processing power
of volunteers' computers around the globe to screen molecules and assess
whether they are
candidate inhibitors of human proteins for cancer treatment. The concept
was simple: ruling out
molecules that were unlikely to be pharmaceutically beneficial meant that
resources could be
efficiently concentrated on a smaller number of more promising molecules.
Screensaver Lifesaver
was an early example of a computational chemistry project of this kind and
remains the largest
such experiment ever conducted. It was very successful, with over 3.5
million personal computers
in more than 200 countries used to screen 3.5 billion separate molecules
for their inhibitory
potential. The project produced a wealth of potential cancer drug leads
for 12 target proteins and,
importantly, revealed for the first time the viability of virtual
screening using a grid of PCs [1].
Screensaver Lifesaver led directly to the spin-out of the company InhibOx
Ltd in late 2001, based
on the Richards-group research.

Subsequent research focused on improving effectiveness in searching the
billions of virtually
accessible compounds. In particular, this focused on enabling
searches with virtual molecules
which `look like' known drug candidates (e.g. a natural drug or an
existing commercial synthetic
compound). The Richards Group made two important advances:

Novel ultrafast computing techniques were needed to help whittle down
the millions of
molecular options more quickly. Techniques were developed to search
databases efficiently
for molecules of similar shape [2, 3]. In particular they used an
approach based on the
moments of distance distributions which improved the speed of
molecular-shape
recognition by at least 3 orders of magnitude. A prospective screening
application of the
method to identify novel inhibitors of arylamine N-acetyltransferases
had a 40% hit rate (ie.
active above a critical limit) and was amongst the most cited articles
in the Journal of the
Royal Society Interface in 2010 [4]. In order to be useful as an
antagonist or agonist of a
target, a small molecule must bind to a specific site on the target. The
method for
identification of this site was the subject of a patent granted to
Richards in 2007 [5].

Virtual screening requires the search procedure to group molecules
with strong
resemblances in terms of electrostatics and lipophilicity as well as
shape. In 2010 - 2011
the Richards Group developed and published innovative solutions to this
problem [6]. At the
time, the most widely-used methods for this type of virtual screening
involved a molecular
alignment step that was computationally intensive and thus provided a
constraint on the
size of database that could be searched. The new methods developed an
alignment-free
approach that was orders of magnitude faster, while maintaining
accuracy. By introducing
partial charge information as a 4th dimension the
electrostatics was handled very efficiently.

These key advances, together with additional developments at InhibOx
allowing chirality to be
incorporated into molecular similarity searching (i.e. distinguishing
enantiomers), made it possible
to perform extremely fast searches of a database of billions of compounds
for molecular similarity
incorporating shape, chirality, electrostatics and lipophilicity, all
critical components when
determining potential drug molecules.

Richards was a member of the academic staff at Oxford University until
his retirement in Dec 2007;
the research was continued in the UOA by two University-employed
post-doctoral researchers,
Ballester and Moretti, in collaboration with Richards (at InhibOx since
2008).

References to the research

Asterisked outputs denote best indicators of quality; University of
Oxford authors are underlined.

Details of the impact

Since 2008, InhibOx Ltd. has made important contributions to
computational chemistry in the field
of drug discovery. Taking advantage of cloud computing techniques, the
natural successor to
Screensaver Lifesaver, to increase the scale and speed of its virtual
screening methods, InhibOx
has helped to drive down costs of searching for leads in a way that has
enabled much smaller
companies to enter the field of drug development. InhibOx's key product is
the drug database
Scopius.

After spin-out in 2001, Isis Innovation Ltd. (the technology transfer arm
of the University of Oxford)
exclusively licensed the software technology developed by the Richards
group to InhibOx. From
2004 to 2008, a new round of investment enabled InhibOx to develop initial
versions of the Scopius
database and novel software methods, informed by the lessons learned
regarding the issues of
large scale database construction obtained with Screensaver; in this
period the level of commercial
activity was minimal. At the start of 2008, Scopius consisted of
approximately 3 million molecules;
by the end of the assessment period it contained >112 million
molecules, making it the world's
largest high-quality database of candidate compounds, either commercially
available or
synthesisable in a few steps. InhibOx has also produced an array of more
focused databases for
specialist applications. Since 2008, InhibOx has used ElectroShape, the
ultrafast technique
invented by the Richards Group which incorporates chiral shape
recognition, to further develop the
search software. InhibOx's CEO states that "InhibOx has developed a
comprehensive array of
computer-aided drug design technologies that helped to advance
real-world commercial drug
discovery projects. The contribution of Richards has been fundamental to
this achievement both
through the development of new science and his experience in bridging
the gap between basic and
applied research." [7]

Rather than developing a software product to sell, InhibOx has focussed
on running targeted
database searches for customers, producing lists of potential molecules
that they can use as drug
leads. This has had a particular impact for SMEs. In some fields of drug
discovery, it can cost
billions to bring a drug to market, including an estimated £ 400,000 for a
company to build its own
molecule database in order to find the right molecules to experiment with,
and typically >£ 50M -100M
to develop compounds suitable for use in clinical trials. These high
costs have hindered the
pre-clinical trial phases of drug development, restricting them to very
large, well-financed
companies. InhibOx has enabled increased competition in early-stage drug
R&D by making
compound searching more affordable for SMEs; a target search of molecules
using Scopius costs
around £ 20,000 - a fraction of what it would cost a small company to
build its own database.
InhibOx's client base demonstrates the way in which it has helped to open
up early-stage
development to smaller companies: 75% of its clients are SMEs, e.g.
DormaTarg, Mission
Therapeutics, Lauras and Cephalon, and 25% are corporates, e.g. Bristol
Myers Squibb and
Colgate Palmolive. This reflects and supports a shift in the way the
market operates; big pharma
will in some cases buy drug leads from small companies rather than develop
leads themselves.
Lauras' Vice President for R&D commented that InhibOx has helped
redesign the company's drug
targeting programmes and suggested new lines of derivatisation that have
delivered compounds
with the properties they wanted [8]. Likewise DormaTarg worked with
InhibOx on in silico
screening, testing several of the hits predicted by InhibOx, and finding
that several showed the kind
of novel activity they were seeking [9].

In 2010 InhibOx designed a programme to develop Tumour Necrosis Factor-α
Converting Enzyme
inhibitors for inflammatory disease starting from a non-selective weak
lead molecule. Using
InhibOx structure-based design technology and project management
expertise, a cost-effective
semi-virtual discovery project delivered a novel compound series and
optimised a lead candidate
requiring the synthesis of only 33 compounds within a 6-month timescale.
The series (based on
bicyclosulfonyl acid compounds) was patented by InhibOx [10], and the
programme was sold in
December 2010 to a large EU-based pharmaceutical company. This is an
example of InhibOx
providing the initial screening of compounds that are now being taken
forward in further research.

More recently InhibOx has taken advantage of the experience developed in
its pioneering use of
cloud computing for large-scale molecular modelling. The availability of
new and powerful cloud
computing services which can be leveraged on demand has enabled InhibOx to
provide large-
scale virtual screening throughput at low cost for specific purposes. In
2012, the company created
a corporate virtual library for a major corporation based on their
available chemistry. The result
contained over 28 million drug-like molecules and was completed in just
over 4 days using cloud
computing facilities from Amazon Web Services (AWS). The computational
cluster constructed
would have ranked the project in the Top 500 Supercomputers, with a speed
to 240 TFlop/s.;
constructing this level of hardware infrastructure in-house would have
cost InhibOx around $ 200k,
so the use of AWS led to considerable cost savings. This work was
highlighted in a case study on
the AWS web site [11]. Company expertise in this area is reflected in a
recent review by InhibOx
authors analysing the applications of cloud computing to molecular
modelling [12].

InhibOx has made a conscious decision to remain focussed and concentrate
on core areas of
expertise, a strategy which has helped it to weather the upheaval in the
pharmaceutical industry
while many larger biotechs have gone out of business. It has maintained
steady business during
the impact period; income and investment since 2008 has totalled around £
2.8M, including sales
revenue of £ 250,000 in 2012. It is an export-led company with 60% of
sales in the US, 25% in
Europe and 15% within the UK [7]. Since 2008, it has established an
additional office in Princeton,
USA and since 2010 developed commercial partnerships with the Cambridge
Crystallographic
Data Centre, Intelligensys, COSMIC Discoveries and Molport [13]. These
companies provide
complementary expertise in virtual screening, computer-aided drug
discovery and chemical
compound manufacture. The Scientific Director of Intelligensys has
outlined the benefits to them
(and to drug discovery generally) of the partnership: `We have seen,
over many years, too many
seemingly promising lead compounds fail to make it through preclinical
tests. This has been
expensive to the industry and is largely avoidable. This collaboration
is delivering the capability to
stem these losses and deliver much more cost-effective drug discovery as
a result.' [14].

InhibOx's innovation, underpinned by the Richards' Group work, has led to
it being selected as a
partner on several high-profile EU projects such as a recent FP7 framework
grant worth € 1M to
InhibOx [15], and its innovation/international excellence was recognised
in May 2011 with InhibOx
being short listed for the prestigious Red Herring 100 Award — a mark of
distinction for identifying
promising new companies and entrepreneurs. Red Herring is a global media
company with a focus
on technology innovation [16].

Sources to corroborate the impact

The CEO of InhibOx can corroborate the benefits to the company of the
Richards Group
research, details relating to the Scopius database, and income, investment
and sales figures.

http://www.inhibox.com/node/23
Quote on the InhibOx website from the VP for R&D at Lauras AS,
corroborating the fact that
InhibOx's in silico screening has helped Lauras advance its drug
discovery pipeline.